PROJECT SUMMARY/ABSTRACT Current DLBCL treatment options are effective for only 50-60% of cases while many patients still relapse after initial treatment and become chemoresistant. Therefore, treatment strategies designed to specifically inhibit proteins that confer proliferation and self-renewal capacities to lymphoma cells are urgently needed. This proposal will examine the role of LSD1, a key epigenetic regulator in lymphoma formation, growth and regeneration. During the K99 mentored phase of this award the principal investigator (PI) will combine the tools and preliminary results generated during the postdoctoral training in the Melnick lab, with newly acquired skills and advanced techniques developed in the laboratory of Scott Lowe to answer fundamental questions revolving around the role of the epigenetic modifier LSD1 in lymphomas. Aim 1 will determine the contribution of LSD1 activity in DLBCL lymphoma onset, growth and tumor maintenance. The research plan will rigorously explore the role of LSD1 in lymphoma cell survival and describe the LSD1 biochemical functions on transcription and chromatin. Moreover, the proposed experiments will determine how LSD1 contributes to lymphoma formation, will describe any LSD1 functions required for the persistence of established lymphomas, and will identify the specific domain(s) of LSD1 that are essential for the prosurvival LSD1 effect in lymphoma cells. Aim 2 will define LSD1 as a genetic dependency in KMT2D mutant lymphoma. KMT2D is one of the most frequently mutated genes and a tumor suppressor in lymphomas. This aim will explore LSD1 as a genetic vulnerability in KMT2D mutant lymphomas. LSD1 functions in lymphoma may oppose KMT2D activity through enzymatic or protein scaffolding mechanisms. This aim will describe the mechanisms of LSD1 and KMT2D interplay in KMT2D wild type versus mutant lymphomas and identify gene signatures associated with KMT2D-LSD1 regulation that are linked to KMT2D mutation status. Notably, this study will determine if LSD1 targeting could be harnessed for the design of specific therapeutic strategies for these tumors by evaluating the efficacy of LSD1 targeting strategies, including LSD1 inhibitors and decoy LSD1 peptides, in wild type or KMT2D mutant lymphomas. The proposed training program will advance the PI research training in the study of epigenetic deregulation and self-renewal and prepare her towards becoming an independent investigator. During the independent phase, the PI will take advantage of the developed tools to explore a novel research direction focusing on the role of LSD1 in lymphoma self renewal using serial replating assays and limiting dilution assays. Overall, this work will definitively determine the mechanisms of LSD1 function in lymphomas, evaluate LSD1 lymphoma dependency and provide the basis to independently study self-renewal in lymphomas.